1. Field of Invention
The present invention relates to magnetically controllable delivery systems and methods of using thereof to attract and deliver therapeutic agents attached to, or encapsulated within, magnetic particles (i.e., carriers) at selected sites in a body or a subject. More specifically, this invention relates to the use of two sources of magnetic force to deliver therapeutic agents including cells by utilizing magnetizable particles associated with the therapeutic agents.
2. Description of Related Art
The best approach for treating tumors and other localized ailments is to administer drugs only at the site of complication. By delivering the drug locally, the toxicity of the drug to the rest of the body can be reduced while maintaining the desired therapeutic benefit at the site of the ailment. Many drugs developed by the pharmaceutical industry have shown remarkable success during in vitro testing and animal trials, but have yielded undesirable results in clinical trials due to systemic toxicity of the drug to the body. Thus, the ability to deliver large concentrations of drugs locally (i.e., only at the site of the ailment) is of major importance for both the pharmaceutical industry and for clinicians.
However, known drug delivery vehicles are not capable of local delivery of high concentrations of drugs by minimally invasive techniques. This is especially true when repeat dosing is required. The magnetic delivery system described herein overcomes many of these difficulties, and provides a method for concentrating drugs at selected sites in the body with minimal stress on the patient.
Stents are commonly used in a variety of biomedical applications. For example, stents are routinely implanted in patients to keep blood vessels open in the coronary arteries, to keep the esophagus from closing due to strictures of cancer, to keep the ureters open for maintenance of kidney drainage, and to keep the bile duct open in patients with pancreatic cancer. Such stents are usually inserted percutaneously under radiological guidance.
Stents comprise a tube shaped object made of metal (e.g., 316 L Stainless Steel), an alloy (e.g., Nickel-Titanium) or polymer (e.g., polyurethane), in a wide range of physiologically appropriate diameters and lengths, which are inserted into a vessel or passage to keep the lumen open and prevent closure due to a stricture or external compression. General stent design varies in the number of intersections and the interstrut area, the in-strut configuration, and the metal-to-artery ratio. The two different expansion principles for stents are balloon-expansion and self-expansion, and the design types can be categorized into five types: ring, tubular, multi-design, coil, and mesh (Regar et al. Br. Med. Bull. 2001 59:227-48; Hehrlein et al. Basic Res. Cardiol. 2002 97:417-23; Gershlick et al. Atherosclerosis 2002 160:259-71; Garas et al. Pharmacology and Therapeutics 2001 92:165-78).
Stents have been routinely used over the last ten years in percutaneous transluminal coronary angioplasty (PTCA), a procedure for the treatment of severe, symptomatic coronary stenosis (Garas, S. M. et al. Pharmacology and Therapeutics 2001 92:165-178). The PTCA procedure was first introduced in the 1970s as an alternative to coronary-artery bypass surgery for the clearing of coronary vessels blocked by plaque. PTCA has proven to be a much less invasive procedure, with patients able to return to work the week following the procedure, as opposed to the lengthy hospital stay required with bypass surgery (Fricker, J. Drug Discovery Today 2001 6:1135-7). Stents are used extensively in PTCA procedures due to their unique ability to master a major complication of balloon angioplasty ((sub) acute vessel closure), and a superior long-term outcome in comparison to balloon angioplasty (Regar et al. Br. Med. Bull. 2001 59:227-48).
However, in-stent restenosis (the re-closing of the vessel) remains a major limitation, particularly in coronary stenting. Restenosis is generally considered a local vascular manifestation of the biological response to injury. The injury as a result of catheter insertion consists of denudation of the intima (endothelium) and stretching of the media (smooth muscle). The wound-healing reaction consists of an inflammatory phase, a granulation phase, and a remodeling phase. The inflammation is characterized by growth factor and platelet activation, the granulation by smooth muscle cell and fibroblast migration and proliferation into the injured area, and the remodeling phase by proteoglycan and collagen synthesis, replacing early fibronectin as the major component of extracellular matrix. Coronary stents comprise mechanical scaffolding that almost completely eliminates recoil and remodeling. However, neo-intimal growth or proliferation is still a problem. Neo-intimal proliferation occurs principally at the site of the primary lesion within the first 6 months after implantation, a major checkpoint for patient health post-surgery (Regar et al. Br. Med. Bull. 2001 59:227-48). Neo-intima forms during the first week after PTCA and the progress is well under way after 4 weeks, with continued progression over the following months (Hehrlein et al. Basic Re. Cardiol. 2002 97:417-23). This neo-intima is an accumulation of smooth muscle cells within a proteoglycan matrix that narrows the previously enlarged lumen. Its formation is triggered by a series of molecular events including leukocyte infiltration, platelet activation, smooth muscle cell expansion, extracellular matrix elaboration, and re-endothelialization (Regar et al. Br. Med. Bull. 2001 59:227-48).
Three major drug delivery techniques under consideration for the prevention of restenosis are (i) prevention of thrombus formation; (ii) prevention of vascular recoil and remodeling; and (iii) prevention of inflammation and cell proliferation (Garas et al. Pharmacology and Therapeutics 2001 92:165-78). In vitro and in vivo animal model experimentation has shown promise in all three categories, mainly in antiproliferation treatments. However, clinical success has been limited (Garas et al. Pharmacology and Therapeutics 2001 92:165-78), primarily due to systemic toxicity.
Local drug delivery provides limited systemic release, thereby reducing the risk of systemic toxicity. Known techniques for local drug delivery include direct coating of the stent with drug, coating of the stent with a drug-containing biodegradable polymer, and hydrogel/drug coating. Biodegradable stents have also been described (Regar et al. Br. Med. Bull. 2001 59:227-48; Hehrlein et al. Basic Res. Cardiol. 2002 97:417-23; Gershlick et al. Atherosclerosis 2002 160:259-71; Garas et al. Pharmacology and Therapeutics 2001 92:165-78; Schwartz et al. Circulation 2002 106:1867-73; Fricker, J. Drug Discovery Today 2001 6:1135-7). Problems with these technologies, however, include the inflammatory response generated due to large polymer concentrations, the inability to deliver effective concentrations, one-time dosage limitations, and, in the case of the biodegradable stent, mechanical compromise. An additional concern with the polymer-coated drug-eluting stents is limitation of the growth of the cell layer necessary to cover the stent and prevent the bare metal from coming in long contact with the blood, thereby leading to clot formation (Schwartz et al. Circulation 2002 106:1867-73; Fricker, J. Drug Discovery Today 2001 6:1135-7).
The ability to apply forces on magnetic particles with external magnetic fields has been harnessed in various biomedical applications including prosthetics (Herr, H. J. of Rehab. Res. and Devel. 2002 39(3):11-12), targeted drug delivery (Goodwin, S. J. of Magnetism and Magnetic Materials 1999 194:209-217) and antiangiogenesis strategies (Liu et al. J. of Magnetism and Magnetic Materials 2001 225:209-217; Sheng et al. J. of Magnetism and Magnetic Materials 1999 194:167-175). U.S. Pat. No. 4,247,406 describes an intravascularly-administrable, magnetically-localizable biodegradable carrier comprising microspheres formed from an amino acid polymer matrix containing magnetic particles embedded within the matrix for targeted delivery of chemotherapeutic agents to cancer patients. Microspheres with magnetic particles, which are suggested to enhance binding of a carrier to the receptors of capillary endothelial cells when under the influence of a suitable magnetic field, are also described in U.S. Pat. No. 5,129,877.
U.S. Pat. Nos. 6,375,606; 6,315,709; 6,296,604; and 6,364,823 describe methods and compositions for treating vascular defects, and in particular aneurysms with a mixture of biocompatible polymer material, a biocompatible solvent, adhesive and preferably magnetic particles to control delivery of the mixture. In these methods, a magnetic coil or ferrofluid is delivered via catheter into the aneurysm. This magnetic device is shaped, delivered, steered and held in place using external magnetic fields and/or gradients. This magnetic device attracts the mixture to the vascular defect wherein it forms an embolus in the defect thereby occluding the defect.
A model for inducing highly localized phase transformations at defined locations in the vascular system by applying 1) external uniform magnetic fields to an injected superparamagnetic colloidal fluid for the purpose of magnetization and 2) using embedded particles to create high magnetic field gradients was described by inventors (Forbes et al. Abstract and Poster Presentation at the 6th Annual New Jersey Symposium on Biomaterials, Oct. 17-18, 2002, Somerset, N.J.). This work describes the use of uniform magnetic fields in combination with large magnetic particles (greater than 2 micron in diameter) to form chains along the direction of applied field and in turn use this to embolize micro-vessels (50-100 microns in diameter). The use of these magnetizable implants in drug delivery was also described previously by authors Z. Forbes, B. B. Yellen, G. Friedman, and K. Barbee (IEEE Trans. Magn. 39(5): 3372-3377 (2003)).
Known methods and devices for delivery of magnetizable drug or agent-containing magnetic carrier to specific locations in the body rely upon a single source of magnetic field to both magnetize the carriers and to pull them by magnetic force to the specific location. Previous attempts to use magnetic particles in these applications have relied on high gradient magnetic fields produced by magnets external to the body to direct magnetic particles to specific locations (see Flores, 2002; Gallo, et al., (1997); Lübbe, et al., (2001); Mossbach, et al., (1979); Rudge, et al., (2001)). The main disadvantage of this approach is that externally generated magnetic fields apply relatively small and insufficiently local forces on micron and nano-scale magnetic particles, and thus these methods have limited applications.
Chen (U.S. Pat. No. 5,921,244) discloses inserting a magnet (an electromagnet or a permanent magnet) or a plurality of magnets into an opening in a body to attract magnetic fluid/particles. The plurality of magnets is described to be disposed along the longitudinal axis of the magnetic probe. The plurality of magnets actually forms a larger magnet. Chen does not describe using a plurality of sources of magnetic fields or simultaneously creating a far penetrating field and a strong magnetic field gradient, which cannot be accomplished with a single source.
Gordon (U.S. Patent Publication No. US 2002/0133225) describes a device comprising an implant having a magnetic field and a medical agent carried by a magnetically sensitive carrier. The carrier is introduced into the blood flow of the organism upstream from the target tissue, and the carrier and medical agent migrate via the blood flow to the target tissue. Gordon discloses an implant comprising a magnetized material (e.g., a ferromagnetic or a superparamagnetic material). Examples describe making a stent from ferromagnetic materials and magnetized by using an external magnet or made from a magnetized material. Gordon does not disclose optimizing the surface of the implant for providing a stronger magnetic field gradient. Gordon does not describe using a plurality of sources of magnetic fields.
Single source capture methods, however, are at odds with the underlying physics of magnetic particle capture, which depends on the simultaneous imposition of very strong far-reaching magnetic fields and strong spatial magnetic field gradients. The purpose of the far-reaching field is to increase the magnetic moment of individual drug-containing particles in the vicinity of the field to the point of magnetic saturation. Far-penetrating fields are most typically generated with large magnetic sources. However, the force on a magnetized particle also depends on production of strong magnetic field gradients, which are most easily generated with very small magnetic sources. Thus, the ability to simultaneously produce far-penetrating magnetic fields that have strong magnetic filed gradients is very difficult to accomplish with a single source. For this reason, Chen teaches use of relatively large electromagnets implanted in tissue beds to attract magnetic fluid circulating within the blood vessels that are relatively far away, which is a less effective method for capturing magnetic carriers.
The current invention recognizes that the ability to simultaneously produce far-penetrating magnetic fields that have strong magnetic filed gradients is very difficult to accomplish with a single source and offers solutions to this problem. The present invention further differs from previous techniques in that the goal is to deliver therapeutic agents to a desired tissue site without obstructing flow through the blood vessel.
Despite the foregoing developments, there is still a need in the art for improved methods of delivery of therapeutic agents utilizing magnetic forces.
All references cited herein are incorporated herein by reference in their entireties.